What Is Amyloidosis?

Amyloidosis is a disease that occurs when a substance known as amyloid builds up in tissues and organs. Amyloid is formed from the breakdown of normal or abnormal proteins. The amyloid that is derived from these breakdown products deposits between the cells of one or more of the body's organs and interferes with the way the organs work. Deposits of amyloid in the heart cause the disease known as cardiac amyloidosis: as the deposits increase, the heart gets increasingly stiff and eventually the pumping function deteriorates. There are several types of amyloidosis, and the different forms are derived from different proteins. It is extremely important to determine the specific type of amyloid causing the disease, because each type of amyloidosis progresses at a different rate, and the treatment differs greatly for each form. Although amyloid can affect many organs of the body simultaneously, this overview specifically addresses the consequences and treatment of amyloid deposition in the heart.

Features of Amyloid Heart Disease

Regardless of the underlying type of amyloid, untreated patients with cardiac amyloidosis experience a progressive increase in the thickness of the cardiac walls. This often results in excess buildup of fluid in the body, a condition known as congestive heart failure, The most common symptoms include shortness of breath (sometimes worse when lying down) and swelling of the legs and abdomen. A feeling of pressure or discomfort in the chest during exertion (commonly referred to as angina) can be due to amyloid deposits in the blood vessels of the heart.

Because amyloidosis is often not limited to the heart, symptoms due to other organ involvement may occur, and these include tingling and numbness in the hands and feet (due to nerve damage), carpal tunnel syndrome, dizziness on standing, foamy urine (caused by protein leak in the urine), and unexplained bruising (especially around the eyes). Weight loss, due to loss of muscle, often occurs, but this can be masked by retention of fluid.

Types of Amyloidosis Affecting the Heart

There are 2 main forms of amyloidosis that significantly affect the heart.

AL Amyloidosis

AL amyloidosis is an acquired disease; it is not contagious or inherited. The abbreviation AL stands for Amyloidosis formed from Light chains, and it is a disease of the bone marrow. A specific cell in the bone marrow, known as a plasma cell, normally produces good proteins (antibodies) that help the immune system to fight infection. In AL amyloidosis, plasma cells do not function properly. They producean abnormal amount of a portion of the proteins that make up antibodies, known as light chains. These light chains circulate in the blood and break down to form amyloid deposits in various tissues of the body. About 2000 to 3000 new cases of AL amyloidosis occur each year in the United States, two thirds of these patients are male, and almost all of them are over the age of 50 (although the disease occasionally occurs in younger patients). AL amyloidosis usually involves >1 organ and, without appropriate treatment, it may progress rapidly. It is particularly important to diagnosis AL cardiac amyloidosis early, because it is a life-threatening disease, and untreated patients with involvement of the heart tend to have the most rapid disease progression. The treatment of AL cardiac amyloidosis is discussed below.

Transthyretin-Related Amyloidosis

Transthyretin-related (TTR) amyloidosis is derived from to transthyretin, a small molecule mainly produced by the liver. There are 2 types of TTR-related amyloidosis: a genetic form known as hereditary transthyretin-related amyloidosis, or ATTR, and a nonhereditary form called senile systemic amyloidosis (SSA). ATTR occurs as a result of an inherited defect in the TTR protein. The genetic abnormality can be inherited through either an affected mother or father, and the offspring of a person with this genetic abnormality has a 50% chance of inheriting it. Although not everybody with the abnormal gene will develop TTR amyloidosis, most people seem to do so. Although the TTR mutation is present from birth, the protein functions normally until adult life and then, usually between 30 and 60 years of age, it starts to break down and causes amyloidosis. By that time, an individual with the abnormal TTR gene may already have children and, therefore, may have passed the gene to their children. The manifestation of the disease mainly depends on the specific genetic abnormality in the TTR molecule. Some patients with ATTR mainly have nerve disease (neuropathy), others have cardiac amyloidosis, and the remainder have a combination of both. ATTR is a more slowly progressive disease than AL amyloidosis, and most untreated affected individuals live many years after the first signs of the disease.

SSA results from the breakdown of the normal TTR molecule. It is a slowly progressive disease that usually affects the heart of men, almost always in their seventies or eighties (hence, the adjective “senile”). It is not known why the normal TTR molecule produces amyloid in patients with SSA, but when the disease occurs it is almost always limited to the heart, and, like the other forms of amyloidosis, it never affects the brain. Because the heart is the only clinically affected organ, the first sign of SSA is usually leg swelling or shortness of breath, both of which are symptoms of congestive heart failure. Interestingly, many patients with SSA give a history of hand tingling and numbness due to carpal tunnel syndrome (compression of a nerve in the hand). In these patients, the carpal tunnel syndrome is due to amyloid deposition, and the symptoms often occur several years before the cardiac symptoms. Carpal tunnel syndrome is seen in other types of amyloidosis, but probably with less frequency than SSA.

Diagnosing Cardiac Amyloidosis

Because cardiac amyloidosis is uncommon, and the early symptoms may be nonspecific, there is often a delay in making the diagnosis. Nevertheless, there are features of the disease in the medical history, found on physical examination or present in basic cardiac tests that can point to a diagnosis of this disease. In a patient with symptoms of congestive heart failure, the finding of thick heart walls on a cardiac ultrasound (echocardiogram) may indicate infiltration of the heart with amyloid, particularly if there is no other heart condition that could account for this. If the voltage is lower than normal on an ECG in the setting of thick walls on an echocardiogram, a diagnosis of cardiac amyloidosis should be very strongly considered. A typical echocardiogram from a patient with amyloidosis, in comparison with a healthy subject, is shown in Figure 1. Cardiac MRI is also useful for diagnosing cardiac amyloidosis, particularly when performed with the use of the gadolinium as an imaging agent. Recently, a nuclear scan known as a technetium pyrophosphate scan has been shown to be helpful in increasing the suspicion of TTR or SSA amyloidosis; in patients with this condition, the radioisotope is taken up by the heart giving an appearance rarely seen in other diseases.

Comparison of an echocardiogram (ultrasound of the heart) in a healthy patient (left) and a patient with cardiac amyloidosis (right). In amyloidosis, the walls of the heart are thickened, resulting in a stiff heart, eventually with poor pumping function. The main pumping chamber, the left ventricle (LV), is reduced in size because of the thick walls. RV indicates right ventricle; Ao, aorta; LA, left atrium. Note how the septum separating the LV from the RV is much thicker in the patient with amyloidosis than in the healthy subject. This is due to the amyloid in the heart wall.

Once the disease is suspected, a definite diagnosis of amyloidosis is needed. In general, this requires the demonstration of amyloid deposits in the tissues. This can be achieved by taking a biopsy from any organ suspected of being involved with amyloidosis. The easiest way to get a sample to test for amyloid is to stain and examine a small piece of abdominal fat under a microscope. To do this, a local anesthetic is used to numb the skin of the abdomen, and a small core of fat is removed with a needle. Although the technique is simple, amyloid is not always found in the fat, and a skilled pathologist is needed to read the results. In suspected amyloidosis of the heart, a cardiac biopsy is often performed: after numbing an area of the neck with a local anesthetic, a thin, flexible wire with a tiny pincerlike end (a bioptome), is passed through a vein into the right ventricle of the heart, where (under x-ray and ultrasound guidance to safely position the bioptome) 4 or 5 pinhead-size pieces of heart muscle are taken. The procedure is painless and, in skilled hands, is safe. If amyloid is present, it will always be seen on the heart biopsy, and there is usually enough tissue available to perform special techniques needed to precisely determine the amyloid type. An example of a cardiac biopsy showing amyloid deposition is shown in Figure 2.

Cardiac biopsies (original magnification ×400) showing normal findings (left) and extensive amyloid infiltration (right). In the normal heart, the muscle fibers (stained pink in this slide) are close together with little space between them. In the patient with amyloidosis, the muscle fibers, staining here in red, are disrupted by a large amount of amyloid deposited between them (staining light pink-purple). (Images courtesy of Dr Paul VanderLaan, Brigham and Women's Hospital Department of Pathology).

It is critical to know what type of amyloid is present to plan the appropriate treatment. Each type of amyloidosis can be detected by specific tests, either by special stains of a biopsy, blood tests, or both.

For AL amyloidosis, a test known as immunofixation can determine the presence of abnormal proteins in blood or urine, and a blood test known as a free light chain assay is used to quantify the amount of these abnormal proteins. The free light chain assay is also used to follow the response to treatment in AL amyloidosis. If AL amyloidosis is suspected, a bone marrow biopsy is usually performed to examine the number of plasma cells. If there is no evidence of AL amyloidosis, blood can be drawn to determine the presence of a mutation in the TTR. If this is negative, but TTR amyloidosis is suspected, the most likely diagnosis is SSA. In this case, and in certain other situations, special staining of the biopsy tissue is often helpful to distinguish among the different amyloid types, but occasionally the biopsy needs to be sent to a specialized laboratory to determine the molecular structure of the amyloid protein.

Several rarer forms of amyloid deposits exist that may occasionally affect the heart. These are outside the scope of this summary, but, if suspected, they can be investigated at a skilled amyloidosis center.

Treatment of Cardiac Amyloidosis

Management of cardiac amyloidosis is best performed in a center specializing in the disease, or at least in consultation with such a center. Treatment requires a twofold approach: management of cardiac-related complications due to amyloid deposition (which is similar regardless of the specific type of amyloid) and treatment of the underlying disease to suppress new amyloid formation (which is targeted for each specific form).

Treatment of Cardiovascular Complications

Patients with cardiac amyloidosis avidly retain fluid and are very sensitive to sodium intake. It is very important to limit the salt intake to no more than 2000 mg (2 g), and ideally to 1500 mg, daily. This requires reading nutrition labels on food carefully, not adding salt to food, and avoiding eating in restaurants. Daily weighing can be helpful: a weight gain of 2 or more pounds over 1 to 2 days can mean there is too much fluid in the body. Diuretics (medications that remove excess sodium and fluid from the body) are the main drugs of therapy for amyloid-related symptoms. Commonly used diuretics include furosemide and torsemide. A booster diuretic, metolazone, can be used intermittently if fluid retention is severe, and daily use of spironolactone in addition to the furosemide or torsemide often helps to keep the potassium level normal. Heart involvement in amyloidosis requires frequent follow-up with a cardiologist skilled in the management of heart failure. Patients with cardiac amyloidosis may be unusually sensitive to the side effects of common cardiac drugs, and some drugs that are safe for other patients can cause problems in those with cardiac amyloidosis and must be administered with extreme caution. In general, digoxin should be avoided because it is of little benefit to help heart failure and may have toxic effects. Calcium channel–blocking drugs, particularly diltiazem and verapamil, should be avoided and β-blockers (eg, carvedilol and metoprolol) probably have little positive effect and may lower the blood pressure excessively. Angiotensin-converting-enzyme inhibitors (eg, captopril and lisinopril), are often poorly tolerated in AL amyloidosis, because they can cause a severe drop in blood pressure, but, if tolerated, they can be used in low doses. Anticoagulation therapy with warfarin, dabigatran, or rivaroxaban in patients with atrial fibrillation is highly recommended owing to a high risk of stroke. These drugs occasionally will be recommended even if the cardiac rhythm is normal.

Patients with TTR amyloidosis may develop a slow heart rate, necessitating pacemaker implantation, but there is little evidence that the implantation of a defibrillator to prevent sudden death plays any role in the majority of patients with cardiac amyloidosis.

Treatment of the Underlying Condition

To prevent disease progression, it is critical to address the abnormality that leads to the production of the amyloid protein. The treatment for AL amyloidosis is entirely different from that of TTR or SSA.

AL Amyloidosis

The aim of specific therapy is to stop the production of the abnormal light chains by the plasma cells. This can be achieved by a variety of chemotherapy drugs and related agents. Because each patient is different, the dosage and choice of agent or agents requires careful assessment by a hematologist skilled in the management of AL amyloidosis, in conjunction with a cardiologist who can make sure that any adverse side effects are treated and minimized. An initial therapy is often changed if there is no clear response over the first 2 to 3 cycles. The details of specific therapies are not given here, but the Table shows the drugs commonly used and lists the commoner side effects. In some cases with relatively mild AL cardiac amyloidosis, a patient may be offered high-dose chemotherapy with autologous bone-marrow transplant. For this treatment, the bone marrow is taken from the patient before chemotherapy is given and is reinjected after the chemotherapy to prevent prolonged damage to the bone marrow. This is an effective but toxic therapy, and very careful patient selection is needed.

The response to treatment for AL amyloidosis is assessed by measuring the free light chains in the blood. The levels will return toward normal in successful treatment, usually before there is any definite improvement in the symptoms. Two other specialized blood tests (in addition to standard blood tests) are often monitored in cardiac amyloidosis, N-terminal pro-brain natriuretic peptide (or the related brain natriuretic peptide) and troponin. These tests measure different aspects of heart function, and their results tend to improve if the therapy is working.

ATTR (Familial Amyloidosis)

Because the main source of transthyretin is the liver, liver transplantation is currently the treatment of choice in carefully selected patients whose disease is not too far advanced. Liver transplantation is a major operation, with a need for lifelong therapy to prevent organ rejection by the body's immune system, and in patients with significant cardiac disease it may not be effective unless the heart is also transplanted. Intensive investigation is underway to develop and test drugs that can prevent the production of amyloid in patients with the abnormal gene. These drugs, if effective, may abolish the need for liver transplantation.

Senile Systemic Amyloidosis

SSA is a condition for which no specific treatment currently exists, other than treatment of the effects of the amyloid deposition in the heart. The drugs under investigation for TTR amyloidosis, if effective, should also work in SSA.

Genetic Counseling

The decision to undergo genetic testing (by a blood or saliva test) for family members of a patient with familial amyloidosis is a personal one. We believe that it is important for family members to know whether they are at risk of the disease or not, because they can be monitored closely for the earliest manifestation of the disease onset. Pretesting genetic counseling can be reassuring to family members considering testing, and there are professionals trained in this field, some of whom are affiliated with the major amyloidosis treatment programs. In this context, the new therapies aimed at stabilizing the amyloidogenic proteins may offer a future potential for preventing or delaying the onset of the disease.

Clinical Trials

Because amyloidosis is an uncommon disease, there are often clinical trials of possible therapies. These are usually offered by specialized centers, and an outline of possible trials can usually be found at www.clinicaltrials.gov by searching for the term amyloidosis.

Support Groups and Further Information

There are several patient-run organizations for patients with amyloidosis, and support groups for people with the disease meet in several major US cities. The major groups for patients include The Amyloidosis Foundation (www.amyloidosis.org) and the Amyloidosis Support Groups (www.amyloidosissupport.com). These 2 web sites also have links to overseas treatment centers and support groups.

Sources of Funding

Dr Quarta received funding from the “Istituto Nazionale per le Ricerche Cardiovascolari (INRC),” Italy, and the Brigham and Women's Hospital Cardiac Amyloidosis Fund. Dr Falk received funding from the Brigham and Women's Hospital Cardiac Amyloidosis Fund.

Disclosures

Dr Falk has received funding for consulting with Pfizer Inc, Alnylam Pharmaceuticals, and Isis Pharmaceuticals. The remaining authors have no conflict of interest to disclose.

Acknowledgments

The authors acknowledge Dr Paul VanderLaan, Brigham and Women's Hospital Department of Pathology, for the images in Figure 2 and Shira Falk for her helpful proofreading comments.

Footnotes

The information contained in this Circulation Cardiology Patient Page is not a substitute for medical advice, and the American Heart Association recommends consultation with your doctor or healthcare professional.